Abstract: :
Purpose: We have demonstrated that regulatory T cells (Tregcells) emerge in the spleens of mice that have recovered fromexperimental autoimmune uveoretinitis (EAU). Their presencein the spleen is dependent on an intact eye and the expressionof melanocortin 5 receptor (MC5r). We examined the possibilitythat such Treg cells are involved in the resistance of miceto a reoccurrence of EAU.Methods: EAU was induced by immunizingC57BL/6, MC5r knockout (MC5r-/-), and B10.RIII mice with specificimmunodominant peptides of human interphotoreceptor retinoid-bindingprotein (IRBPp) with complete Freund's adjuvant (CFA). Afterthe uveitis resolved, C57BL/6 and MC5r-/- mice were reimmunizedwith IRBPp emulsified in synthetic adjuvant . For adoptive transferexperiments, T cells from spleens of mice that have recoveredfrom uveitis were activated in vitro with antigen-pulsed antigenpresenting cells. The T cells from the cultures were enrichedfor CD4(+) T cells, and adoptively transferred into syngeneicEAU-susceptible mice. The course and severity of EAU was observedand scored. Adoptive transfer of T cells into EAU-susceptibleB10.RIII mice were depleted of CD25(+) T cells with antibodycoated magnetic beads before the adoptive transfer.Results:Following reimmunization the MC5r-/- mice expressed an acceleratedonset and severe uveitis compared to the delayed and mild uveitisof reimmunized wild type mice. Moreover, the adoptive transferof CD4(+) T cells from wild type mice that recovered from EAUsuppressed the severity of EAU in the MC5r-/- mice. The Tregcells in the spleens of wild type mice that have recovered fromEAU are CD4(+) CD25(+) T cells and are present only after theuveitis begins to show clinical signs of resolving.Conclusions:Mice recovering from EAU express Treg cells whose presence preventsdevelopment of a memory immune response to retinal autoantigen.Our results suggest that the reestablishment of the ocular immunosuppressivemicroenvironment to resolve autoimmune uveitis mediates inductionof regulatory T cells specific to retinal autoantigens.